The invention relates to a novel polyamino acid-catalyzed process for the enantioselective epoxidation of α,β-unsaturated enones and α,β-unsaturated sulfones under two-phase conditions in the presence of specific cocatalysts.
Chiral, nonracemic epoxides are known as valuable synthons for preparing optically active drugs and materials (for example (a) Bioorg. Med. Chem., 1999, 7, 2145–2156; and (b) Tetrahedron Lett., 1999, 40, 5421–5424). These epoxides can be prepared by enantioselective epoxidation of double bonds. In this case, two stereocenters are produced in one synthetic step. It is therefore not surprising that a large number of methods have been developed for the enantioselective epoxidation of double bonds. However, there is still a great need for novel, improved methods for enantioselective epoxidation.
The epoxidation methods limited to the specific substrates in each case include methods for the enantioselective epoxidation of α,β-unsaturated enones.
Thus, for example, the use of chiral, nonracemic alkaloid-based phase-transfer catalysts for the epoxidation of enones is described in Tetrahedron Lett., 1998, 39, 7563–7566, Tetrahedron Lett., 1998, 39, 1599–1602, and Tetrahedron Lett., 1976, 21, 1831–1834.
Tetrahedron Lett., 1998, 39, 7353–7356, Tetrahedron Lett., 1998, 39, 7321–7322, and Angew. Chem., Int. Ed. Engl., 1997, 36, 410–412 furthermore describe possibilities for the metal-catalyzed asymmetric epoxidation of enones using organic hydroperoxides.
WO-A 99/52886 further describes the possibility of enantioselective epoxidation of enones in the presence of catalysts based on sugars. Another method for epoxidation using Zn organyls and oxygen in the presence of an ephedrine derivative has been published in Liebigs Ann./Recueil, 1997, 1101–1113.
Angew. Chem., Int. Ed. Engl., 1980, 19, 929–930, Tetrahedron, 1984, 40, 5207–5211, and J. Chem. Soc. Perkin Trans. 1, 1982, 1317–24 describe what is known as the classical three-phase Juliá epoxidation method. In this method, the enantioselective epoxidation of α,β-unsaturated enones is carried out with the addition of enantiomer- and diastereomer-enriched polyamino acids in the presence of aqueous hydrogen peroxide and NaOH solution and of an aromatic or halogenated hydrocarbon as solvent. Further developments of these so-called three-phase conditions are to be found in Org. Synth.; Mod. Trends, Proc. IUPAC Symp. 6th., 1986, 275. The method is now generally referred to as the Juliá-Colonna epoxidation.
According to EP-A 403,252, it is possible also to employ aliphatic hydrocarbons advantageously in this Juliá-Colonna epoxidation in place of the original solvents.
According to WO-A 96/33183 it is furthermore possible in the presence of the phase-transfer catalyst Aliquat® 336 ([(CH3)(C8H17)3N+]Cl−) and using at the same time sodium perborate, which is of low solubility in water, instead of hydrogen peroxide, for the required amount of base (NaOH) to be reduced, compared with the original conditions of Juliá and Colonna (Tetrahedron, 1984, 40, 5207–5211), from about 3.7 to 1 equivalent.
Despite these improvements, the three-phase conditions have distinct disadvantages. The reaction times under the original conditions are in the region of days even for reactive substrates. For example, 1–6 days are required for trans-chalcone, depending on the polyamino acid used (Tetrahedron, 1984, 40, 5207–5211). A preactivation of the polyamino acid carried out in the reaction vessel, by stirring in the solvent with the addition of NaOH solution for 12 to 48 hours, shortens the reaction time for many substrates to 1 to 3 days. In this case, no intermediate workup of the catalyst is necessary (EP-A 403,252). The preactivation can be reduced to a minimum of 6 h in the presence of the NaOH/hydrogen peroxide system (J. Chem. Soc. Perkin Trans. 1, 1995, 1467–1468).
Despite this improvement, the three-phase method cannot be applied to substrates which are sensitive to hydroxide ions (J. Chem. Soc., Perkin Trans. 1, 1997, 3501–3507). A further disadvantage of these classical conditions is that the polyamino acid forms a gel during the reaction (or even during the preactivation). This restricts the required mixing during the reaction and impedes the working up of the reaction mixture.
Tetrahedron Lett., 2001, 42, 3741–43 discloses that under the three-phase conditions the addition of the phase-transfer catalyst (PTC) Aliquat 336 in the epoxidation of phenyl-E-styryl sulfone leads to only a slow reaction rate (reaction time: 4 days) and a poor enantiomeric excess (21% ee). To date, no example of the use of PTCs for the epoxidation of α,β-unsaturated enones under the classical three-phase Juliá-Colonna conditions has been disclosed.
The Juliá-Colonna epoxidation has been improved further by a change in the reaction procedure. According to Chem. Commun., 1997, 739–740, (pseudo)-anhydrous reaction conditions can be implemented by using THF, 1,2-dimethoxyethane, tert-butyl methyl ether, or ethyl acetate as solvent, a non-nucleophilic base (for example, DBU), and a urea/hydrogen peroxide complex as oxidant. The epoxidation takes place distinctly more quickly under these so-called two-phase reaction conditions. According to J. Chem. Soc., Perkin Trans. 1, 1997, 3501–3507, therefore, the enantioselective epoxidation of hydroxide-sensitive enones under the Juliá-Colonna conditions is also possible for the first time in this way.
However, the observation that, on use of the two-phase conditions, the polyamino acid must be preactivated in a separate process in order to achieve rapid reaction times and high enantiomeric excesses proves to be a distinct disadvantage. Several days are needed for this preactivation, which takes place by stirring the polyamino acid in a toluene/NaOH solution. According to Tetrahedron Lett., 1998, 39, 9297–9300, the required preactivated catalyst is then obtained after a washing and drying procedure. However, the polyamino acid activated in this way forms a paste under the two-phase conditions, which impedes mixing during the reaction and the subsequent workup. According to EP-A 1,006,127, this problem can be solved by adsorbing the activated polyamino acid onto a solid support. Polyamino acids supported on silica gel are referred to as SCAT (silica adsorbed catalysts).
According to EP-A 1,006,111, a further variant of the Juliá-Colonna epoxidation is catalysis of the enantioselective epoxidation by the activated polyamino acid in the presence of water, a water-miscible solvent (for example, 1,2-dimethoxyethane), and sodium percarbonate. However, the use of water-miscible solvents complicates the workup (extraction) in this process.
In the Juliá-Colonna epoxidation, the reaction rate and the enantiomeric excess (ee) that can be achieved depend greatly on the polyamino acid used and the mode of preparation thereof (Chirality, 1997, 9, 198–202). In order to obtain approximately comparable results, a standard system with poly-L-leucine (pII) as catalyst and trans-chalcone as precursor is used throughout for the development and description of novel methods in the literature. However, besides D- or L-polyleucine, other polyamino acids such as, for example D- or L-neopentylglycine are also used successfully (EP-A 1,006,127).
The object of the present invention was to provide a process that makes the homo-polyamino acid-catalyzed enantioselective epoxidation of α,β-unsaturated enones and α,β-unsaturated sulfones possible but is not subject to the disadvantages of the above-described variants of the Juliá-Colonna epoxidation. It was intended in particular to find a rapid and broadly applicable method that avoids the separate, time-consuming and complicated preactivation of the polyamino acid. At the same time, it was intended that the process have advantages in relation to the space/time yield, handling, economics, and ecology on the industrial scale.
It has now been found, surprisingly, that the epoxidation of α,β-unsaturated enones and α,β-unsaturated sulfones can be carried out under two-phase conditions in the presence of a polyamino acid, as catalyst, that has not been subjected to previous separate activation when the epoxidation takes place in the presence of a phase-transfer catalyst. This procedure surprisingly makes it possible for the reaction times to be very short with, at the same time, high enantiomeric excesses.